Hieab H H Adams1, Renée F A G de Bruijn2, Albert Hofman3, André G Uitterlinden4, Cornelia M van Duijn3, Meike W Vernooij1, Peter J Koudstaal5, M Arfan Ikram6. 1. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands. 2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands. 3. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. 4. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. 5. Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands. 6. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address: m.a.ikram@erasmusmc.nl.
Abstract
INTRODUCTION: Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored. METHODS: In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged ≥55 years were genotyped, screened for mild cognitive impairment (MCI) in 2002 to 2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores of genetic variants for Alzheimer's disease (AD), Parkinson's disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) were constructed and investigated for association with MCI and the subsequent conversion to dementia. RESULTS: In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) were amnestic and 213 (5.9%) nonamnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03-1.28]), whereas PD and FTLD/ALS risk scores were associated only with nonamnestic MCI (odds ratios 1.15 [1.00-1.32] and 1.19 [1.03-1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37-1.77]). DISCUSSION: Genetic evidence supports the view that multiple neurodegenerative pathways lead to MCI and that the subsequent conversion to dementia, primarily of the AD subtype, is mainly due to the AD pathway(s).
INTRODUCTION:Neurodegenerative diseases are a major cause of cognitive impairment and can ultimately lead to dementia. Genome-wide association studies have uncovered many genetic variants conferring risk of neurodegenerative diseases, but their role in cognitive impairment remains unexplored. METHODS: In the prospective, population-based Rotterdam Study, 3605 nondemented persons aged ≥55 years were genotyped, screened for mild cognitive impairment (MCI) in 2002 to 2005 and underwent continuous follow-up for dementia until 2012. Weighted polygenic risk scores of genetic variants for Alzheimer's disease (AD), Parkinson's disease (PD), and the frontotemporal lobar degeneration/amyotrophic lateral sclerosis disease spectrum (FTLD/ALS) were constructed and investigated for association with MCI and the subsequent conversion to dementia. RESULTS: In total, 360 (10.0%) persons had MCI, of whom 147 (4.1%) were amnestic and 213 (5.9%) nonamnestic. The AD risk score was associated with both MCI subtypes (odds ratio for all MCI 1.15 [95% CI, 1.03-1.28]), whereas PD and FTLD/ALS risk scores were associated only with nonamnestic MCI (odds ratios 1.15 [1.00-1.32] and 1.19 [1.03-1.37], respectively). The AD risk score, but not PD and FTLD/ALS risk scores, was associated with an increased risk of dementia (hazard ratio 1.55 [1.37-1.77]). DISCUSSION: Genetic evidence supports the view that multiple neurodegenerative pathways lead to MCI and that the subsequent conversion to dementia, primarily of the AD subtype, is mainly due to the AD pathway(s).
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Authors: Vincent Chouraki; Christiane Reitz; Fleur Maury; Joshua C Bis; Celine Bellenguez; Lei Yu; Johanna Jakobsdottir; Shubhabrata Mukherjee; Hieab H Adams; Seung Hoan Choi; Eric B Larson; Annette Fitzpatrick; Andre G Uitterlinden; Philip L de Jager; Albert Hofman; Vilmundur Gudnason; Badri Vardarajan; Carla Ibrahim-Verbaas; Sven J van der Lee; Oscar Lopez; Jean-François Dartigues; Claudine Berr; Philippe Amouyel; David A Bennett; Cornelia van Duijn; Anita L DeStefano; Lenore J Launer; M Arfan Ikram; Paul K Crane; Jean-Charles Lambert; Richard Mayeux; Sudha Seshadri Journal: J Alzheimers Dis Date: 2016-06-18 Impact factor: 4.472